Mitochondria perform numerous essential tasks in the eukaryotic cell such as pyruvate oxidation, the Krebs cycle and metabolism of amino acids, fatty acids and steroids. The primary function of mitochondria is the generation of energy as adenosine triphosphate (ATP) by means of the electron-transport chain and the oxidative-phosphorylation system (the “respiratory chain”). Additional processes in which mitochondria are involved include heat production, storage of calcium ions, calcium signaling, programmed cell death (apoptosis) and cellular proliferation.
Mitochondria are found in all eukaryotes and vary in number and location depending on the cell type. Mitochondria contain their own DNA and their own machinery for synthesizing RNA and proteins. Mitochondrial DNA (mtDNA) has only 37 genes.
Eight to ten million Americans suffer from arterial occlusive disease, with approximately 500 to 1,000 new cases of chronic limb ischemia per million per year. Acute limb ischemia occurs when there is a lack of blood flow to a limb. It is usually due to either an embolism or thrombosis of an artery in those with underlying peripheral vascular disease. Patients with critical ischemia present with rest pain and/or with tissue loss, which can be ulceration, dry gangrene or wet gangrene, occurring in the lower extremities due to atherosclerotic occlusive disease of the iliac, femoral or popliteal arteries.
Peripheral artery disease (PAD) is a condition of the blood vessels that leads to narrowing and hardening of the arteries that supply the legs and feet. The narrowing of the blood vessels leads to decreased blood flow, which can injure nerves and other tissues.
Peripheral arterial disease is caused by arteriosclerosis, or “hardening of the arteries.” This problem occurs when fatty material (plaque) builds up on the walls of arteries. This causes the arteries to become narrower. The walls of the arteries also become stiffer and cannot widen (dilate) to allow greater blood flow when needed. As a result, when the leg muscles work harder (such as during exercise or walking) they cannot get enough blood and oxygen. Eventually, there may not be enough blood and oxygen, even when the muscles are resting.
Critical limb ischemia (CLI) represents a syndrome that is associated with a particularly adverse natural history. Although clinicians increasingly recognize that peripheral arterial disease (PAD) includes a broad range of clinical syndromes, CLI is associated with very adverse short-term limb and systemic cardiovascular outcomes. CLI is not a specific disease per se; rather, it represents a syndrome that may develop from many fundamentally distinct pathophysiological processes, including advanced atherosclerosis, thromboembolism or atheroembolism, in situ thrombosis, and the arteritides, such as thromboangiitis obliterans (TAO, or Buerger's disease). Buerger's disease is manifested by recurring progressive inflammation and thrombosis (clotting) of small and medium arteries and veins of the hands and feet.
Myocardial infarction (MI), a major arterial occlusion disease, is a form of ischemic heart disease. MI is induced by interruption of blood supply to the heart, most commonly due to occlusion of a coronary artery. The resulting ischemia and ensuing oxygen deprivation, if left untreated for a sufficient period of time, may cause damage or death (infarction) of heart muscle tissue.
Clinical improvement and reduced need for amputation, has been reported, in CLI patients receiving autologous bone marrow or mobilized peripheral blood stem cells for stimulation of angiogenesis. While such treatments are currently being tested, practical and scientific pitfalls may limit widespread implementation if efficacy is proven. Hurdles to be overcome include: a) reduced angiogenic potential of autologous cells in aged patients with cardiovascular risk factors; b) adverse effects of bone marrow extraction and G-CSF mobilization; c) need for on-site cellular manipulation (Murphy M P. et al., (1998): Allogeneic endometrial regenerative cells: An “Off the shelf solution” for critical limb ischemia?); and d) risks in stem cell therapy such as inflammation as a result of immune-suppressive treatment, bleeding resulting from low level of platelets after treatment and development of malignancies.
United States Patent Publication No. 20110008310 discloses methods, kits, and compositions for mitochondrial replacement in the treatment of disorders arising from mitochondrial dysfunction.
International Publication No. WO 2013/035101 of the inventors of the present invention discloses compositions of functional mitochondria and uses thereof.
McCully et al. demonstrated injection of isolated mitochondria during early reperfusion for use in cardioprotection (McCully J. D. et al., 2009, Am J Physiol Heart Circ Physiol 296: H94-H105).
There still remains an unmet need for safe and efficient methods of inducing angiogenesis in general and for treating ischemia related diseases in particular.